Sarcoidosis is a disease of unknown etiology, characterized pathologically by noncaseating granulomas which most commonly involve the lung, skin, lymph node and eyes. Studies of T cell receptor gene expression in sarcoidosis patients reveal oligoclonal collections of alphabeta+ CD4+ T cells at sites of granulomatous inflammation, consistent with an antigen-driven process which is MHC-restricted. Sarcoidosis has similar pathologic, epidemiologic, and immunologic features to mycobacterial infections. We performed PCR analysis for 16S rRNA, rpoB and IS6110 in 25 sarcoidosis and 25 control paraffin- embedded specimens and noted evidence of mycobacterial nucleic acids in 60% of the sarcoid granulomas and none of the controls (p<0.00002, chi square). Sequence analysis of the 16S rRNA and rpoB amplicons revealed mycobacterial nucleic acids including the presence of a novel Mycobacterium, genetically similar to M. tuberculosis (MTB) (99% positional identity). Recent immunologic studies also suggest that mycobacteria may be important in sarcoidosis immunopathogenesis. Song et al noted IgG antibodies to recombinant MTB katG in sera from 48% of sarcoidosis patients compared to 0% in sera from PPD negative controls (p=0.0059). Using matrix-assisted laser desorption/ionization time of flight mass spectrometry, they found MTB katG peptides in 75% of sarcoidosis specimens compared to 14% of control specimens (p=0.0006); in situ hybridization localized MTB katG and 16S rRNA DNA inside the sarcoidosis granuloma. More recently, we performed enzyme linked immunospot (ELISPOT) assays on sarcoidosis and control peripheral blood mononuclear cells (PBMC) for immune recognition of mycobacterial katG and ESAT-6 proteins. We found immune recognition of katG or ESAT-6 peptides in 10 of 13 sarcoidosis patients (77%) compared to 1 of 11 PPD negative healthy controls (9%) (p=0.001, Fisher's exact test) and 4 of 5 PPD positive healthy controls (80 %) (p=1.00, Fisher's exact test). The central hypothesis is that sarcoidosis is an immune response to mycobacterial antigens in a genetically susceptible host. One facet of sarcoidosis immunopathogenesis is the successful formation of a trimolecular complex between the T cell receptor (TCR), major histocompatibility complex (MHC) proteins and processed antigens. We propose to 1) confirm and extend molecular genetic evidence for the presence of mycobacteria in sarcoidosis granuloma, 2) to characterize the T cell response to mycobacterial antigens among sarcoidosis patients with acute, resolved, and chronic disease, and 3) to determine the relationship between HLA types associated with a favorable disease course and the quality of the immune response directed against mycobacterial antigens.